Processes and intermediates for preparing indole pharmaceuticals

Abstract

The invention described herein pertains to processes and intermediates for preparing indole containing pharmaceuticals, particularly to processes and intermediates for preparing selective estrogen receptor modulators, such as bazedoxifene.

What is claimed is: 
     
       1. A process for preparing a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 comprising: 
 (d) contacting a compound of the formula 
 
       
         
           
           
               
               
           
         
       
       with an acid; or
 (c) contacting a first compound of the formula 
 
       
         
           
           
               
               
           
         
       
       with a second compound of the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof, and a base; or
 (b) contacting a first compound of the formula 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof, with a reagent capable of converting the hydroxyl group into a leaving group to form a second compound of the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof, where L is the leaving group; or
 (a) contacting a first compound of the formula 
 
       
         
           
           
               
               
           
         
       
       with a second compound of the formula
   Ar 2 —NHNH 2  
 
 
       or a salt thereof; or 
       a combination of any of the foregoing steps; wherein
 Ar 1  and Ar 2  are each aryl, each of which is independently optionally substituted; 
 Ar 3  is a group of the formula 
 
       
         
           
           
               
               
           
         
         wherein n is 2, 3, 4, or 5; and each R N  is independently selected from hydrogen, alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted, or both R N  and the attached nitrogen are taken together to form a cycloheteroalkyl; 
         R A  is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl; 
         R B  is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl; and 
         R 2  is hydrogen, or represents one or more optional substituents. 
       
     
     
       2. The process of  claim 1 , wherein the second compound in step (a) is a salt; and step (a) is performed in the presence of less than about 1 equivalent of a base. 
     
     
       3. The process of  claim 2 , wherein the base is an inorganic base. 
     
     
       4. The process of  claim 1 , wherein the reagent in step (b) capable of converting the hydroxyl group into a leaving group is a halogenating agent. 
     
     
       5. The process of  claim 1 ,
 wherein the base in step (c) is a hydride base. 
 
     
     
       6. The process of  claim 1 , wherein the acid in step (d) is a carboxylic acid. 
     
     
       7. The process  claim 1 , wherein Ar 1  and Ar 2  are each independently a protected phenol. 
     
     
       8. The process of  claim 7 , wherein Ar 1  and Ar 2  are 4-benzyloxyphenyl. 
     
     
       9. The process of  claim 8  further comprising, contacting the compound of the formula 
       
         
           
           
               
               
           
         
       
       with a reducing agent. 
     
     
       10. The process of  claim 9 , wherein the reducing agent is hydrogen gas in the presence of a metal catalyst, and the metal catalyst is palladium on carbon, to provide a deprotected phenol compound of the formula 
       
         
           
           
               
               
           
         
       
     
     
       11. The process of  claim 1 , wherein the compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, has the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. The process of  claim 10 , further comprising crystallizing the deprotected phenol compound in the presence of an acid, or a carboxylic acid, or acetic acid to form an acid addition salt thereof. 
     
     
       13. The process of  claim 1 , wherein R A  is methyl. 
     
     
       14. The process of  claim 1 , wherein R B  is hydrogen. 
     
     
       15. The process of  claim 1 , wherein Ar 3  is a radical of the formula 
       
         
           
           
               
               
           
         
       
     
     
       16. The process of  claim 1 , wherein the first compound of step (c) is of the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       17. The process of  claim 1 , wherein the second compound of step (c) is of the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       18. The process of  claim 1 ,
 wherein the compound of step (d) is of the formula 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       19. The process of  claim 3 , wherein the inorganic base in step (a) is NaHCO 3 . 
     
     
       20. The process of  claim 4 , wherein the halogenating agent of step (b) is PBr 3 . 
     
     
       21. The process of  claim 5 , wherein the hydride base of step (c) is NaH. 
     
     
       22. The process of  claim 6 , wherein the carboxylic acid of step (d) is acetic acid.